PROJECT SUMMARY/ABSTRACT The initial steps in the establishment of neurotypical brain connectivity occur during late embryonic and early postnatal development, and depend on the formation of specific morphological features in neurons. These features include highly branched dendrites, appropriately dense dendritic spines and an adequate number of functional and flexible synapses. Neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorder (ASD) involve disruption of this developmental process, leading to the aberrant neuronal morphology and brain connectivity that characterize these conditions. We have recently described novel loss of function mutations in CC2D1A (coiled-coil and C2 domain containing 1A) that cause ID, ASD, and seizures by an unknown mechanism. This projects aims to identify the specific role of this protein in neuronal differentiation in a cellular model of CC2D1A loss of function. Under normal conditions, we believe that CC2D1A functions as a molecular scaffold, enabling the formation of signaling complexes on endosomes. In this capacity, CC2D1A acts as a critical integrator of extrinsic stimuli, with outputs to multiple signaling pathways. AKT is a kinase that can be activated by many such stimuli, and signals to a diverse array of downstream targets, many of which have been implicated in ID and ASD. Moreover, the AKT signaling pathway is recruited by brain derived neurotrophic factor (BDNF), an important modulator of dendrite morphology and synaptic plasticity during development and in mature neurons. The new data in this proposal show that genetic removal of Cc2d1a causes dysregulation of AKT signaling responses in BDNF-treated cortical neurons. Since BDNF is such an important stimulator of morphological differentiation and plasticity, we will test the hypothesis that removal of Cc2d1a from neurons disrupts the regulation of the events downstream of BDNF. Thus, we anticipate changes in BDNF-dependent dendrite morphogenesis and remodeling. The proposed studies will be complemented by an analysis of AKT recruitment to signal transduction complexes that reside in different subcellular compartments. These experiments will directly demonstrate the consequences of dysregulated BDNF-AKT signaling in Cc2d1a-depleted neurons, and will show the subcellular compartments where hyperactivated AKT resides in these cells. Together, data generated by these experiments will establish the role of Cc2d1a in neuronal morphogenesis and the importance of this protein in regulating BDNF-AKT signaling during these developmental processes.